Laterality of Radiation Therapy in Breast Cancer is Not Associated With Increased Risk of Coronary Artery Disease in the Contemporary Era

Purpose External beam radiation therapy (EBRT) is a critical component of breast cancer (BC) therapy. Given the improvement in technology in the contemporary era, we hypothesized that there is no difference in the development of or worsening of existing coronary artery disease (CAD) in patients with BC receiving left versus right-sided radiation. Methods and Materials For the meta-analysis portion of our study, we searched PubMed, Web of Science, and Scopus and included studies from January 1999 to September 2022. CAD was identified using a homogenous metric across multiple studies included. We computed the risk ratio (RR) for included studies using a random effects model. For the institutional cohort portion of our study, we selected high cardiovascular-risk patients who received diagnoses of BC between 2010 and 2022 if they met our inclusion criteria. We performed a Cox proportional hazards model with stepwise adjustment. Results A pooled random effects model with 9 studies showed that patients with left-sided BC receiving EBRT had a 10% increased risk of CAD when compared with patients with right-sided BC receiving EBRT (RR, 1.10; 95% CI, 1.02-1.18; P = .01). However, subgroup analysis of 6 studies that included patients diagnosed after 1980 did not show a significant difference in CAD based on BC laterality (RR, 1.07; 95% CI, 0.95-1.20; P = .27). For the institutional cohort portion of the study, we found that patients with left-sided BC who received EBRT did not have a significantly higher risk of CAD when compared with their right-sided counterparts (hazard ratios [HR], 0.73; 95% CI, 0.34-1.54; P = .402). Conclusions Our study suggests a historical trend of increased CAD in BC patients receiving left-sided EBRT. Data from patients diagnosed after 2010 in our institutional cohort did not show a significant difference, emphasizing that modern EBRT regimens are safe, and laterality of BC does not affect CAD outcomes in the short term after a BC diagnosis.


Introduction
Breast cancer (BC) is the most common cancer diagnosis in women and the second leading cause of cancer death. 1 The BC mortality rate has declined by 43% since 1989 because of the increased prevalence of breast screening and advancement in effective available treatments. 1 The use of adjuvant external beam radiation therapy (EBRT) in BC treatment has resulted in decreased BC mortality; however, it has also been associated with increased incidence of cardiovascular (CV) events and mortality, 2,3 especially in those with pre-existing CV risk factors. 4Research outlining the cardiotoxic effects of EBRT has led to considerable decreases in radiation dosages delivered to the heart in modern regimens.Despite this advancement, mean doses to the heart still range between 2 and 7 Gy, depending on the laterality of BC. 5,6 The mean heart dose has been noted to be higher in left-sided BC and that has been associated with increased coronary artery disease (CAD) events in women with leftsided BC. 4,7 In order to minimize unintended cardiotoxicity, modern radiation techniques have evolved since the 1980s 8 to minimize radiation to the heart without decreasing clinical effectiveness. 9Techniques such as deep inspiration breath hold (DIBH) and intensity modulated radiation therapy aim to minimize the radiation dose to peripheral organs such as the heart [10][11][12][13][14][15][16][17][18][19] without compromising the radiation dose to the breast [19][20][21][22] and have been proven to be effective.
Given the improvement in radiation delivery technology, we hypothesized that there is no difference in the development of/worsening of CAD in patients with BC receiving left versus right-sided radiation.4][25][26][27][28][29][30] There are significant discrepancies in the technology for BC radiation among studies, lack of adjustment for preventive CV care in the current decade, and lack of data regarding mean/ median heart dose in the cohort studies we included in the meta-analysis.Thus, we supplemented this meta-analysis with a 10-year single-institution data set between 2010 and 2022 to mitigate these issues.

Literature study strategy
This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. 31We performed the systematic literary search in August of 2022 and encompassed 3 databases: PubMed, Web of Science, and Scopus.The search strategy consisted of keywords and standardized MeSH terms as well as Boolean operators ("OR" or "AND").Keywords included "Right or Left" AND "Coronary Artery Disease OR Ischemic Heart Disease OR Cardiac Events OR Cardiovascular Events OR Morbidity" AND "Radiotherapy" AND "Breast Cancer OR Breast Neoplasms."No restrictions were used.

Inclusion criteria
Studies were included if they met the following criteria: (1) published in English; (2) women with BC were the study population; (3) reported CAD events comparing left-sided versus right-sided EBRT in patients with BC; (4) CAD was defined using International Classification of Diseases 9th edition codes 410 to 414 or 10th edition codes I20 to I25; (5) the 2 groups being compared were patients with left-sided BC receiving EBRT and patients with right-sided BC receiving EBRT.

Data extraction and quality assessment
Four blinded reviewers participated in the abstract and full-text screenings.Conflicting decisions were resolved by collaboration between 2 reviewers (L.S. and A.E.).For each selected study, the following data were extracted: author's name, year of publication, geographic location, study type, duration of follow-up, type/stage of BC, radiation protocols, adjuvant therapy, risk factors, number of events, and number of patients.The quality of the included studies was determined by 2 reviewers (L.S. and J.S.) using the New Castle Ottawa scale for cohort studies 32 (Table E1).

Statistical analysis
A random effects model was used to calculate the risk ratio (RR) with a 95% CI.DerSimonian-Laird method was used for estimating between-study variance and fitting the random-effect model.Heterogeneity was assessed using Cochran's Q static and quantified using Higgins Isquare statistic. 33Publication bias and small-study effects were assessed graphically through funnel plots and statistically through regression-based Egger test.A sensitivity analysis using trim and fill analysis was conducted to assess the robustness of the results.A forest plot was used to graphically present the RR of each study as well as pooled RR.A P value of <.05 was considered statistically significant.IBM SPSS and STATA/MP 17.0 (StataCorp) software were used for statistical analysis.

Institutional data set
Patients were selected sequentially from a cohort of patients who received diagnoses of BC between 2010 and 2022 in our institution where EBRT was used on only one side of the chest.This study was approved by the Augusta University Institutional Review Board.

Inclusion criteria
Patients were included if they met the following criteria: 1. Were considered high CV risk prior to treatment based on prior myocardial infarction/stroke or having 3 or more of the following risk factors: age >55 years, hypertension, diabetes, high cholesterol, tobacco use, and family history of early CV disease.The higher risk cohort was a priori selected because the event rates in lower-risk cohorts are <1% annually making institutional sensitivity analysis not feasible because of the required sample size. 34. Received diagnoses of unilateral BC after 2010 3. Did not receive diagnoses of another primary malignancy 4. Received EBRT as part of their treatment regimen 5. Had an accurate record of risk factor data including pre-existing conditions and medications before the date of diagnosis 6. Had accurate information regarding the type and stage of BC and detailed information regarding the treatment protocol as defined by radiation dosage information and chemo/endocrine/immunotherapy the patient was receiving.

Data extraction
Nine researchers participated in data extraction and collected pertinent patient information from electronic medical records.For each patient, the following data were extracted: demographic information (name, medical record number, gender, race, date of birth, body mass index [BMI], and age at diagnosis), prior risk factors (history of hypertension, hypercholesterolemia, smoking, diabetes, heart failure, atrial fibrillation, atrial flutter, myocardial infarction, cerebrovascular accident or transient ischemic attack, renal function, CAD, peripheral artery disease, chronic obstructive pulmonary disease, rheumatologic disease, hypothyroidism, and depression), cancer information (date of diagnosis, laterality, stage, ductal, tumor/node/metastasis status, ER/PR/HER2 status, date of chemotherapy, date of radiation therapy, date of hormone therapy, date of immunotherapy, type of radiation, total radiation dose, HER2 agents, and type of surgery), baseline vitals, laboratory tests and imaging at cancer diagnosis (BMI, systolic blood pressure, diastolic blood pressure, heart rate, chest computed tomography, ejection fraction, global longitudinal strain, atrial size, potassium, aspartate aminotransferase, alanine transaminase, creatinine, glucose, hemoglobin, neutrophil count, lymphocyte count, white blood cell count, C-reactive protein, A1c, total cholesterol, triglycerides, high density lipoprotein, and allostatic load) and CAD events (myocardial infarction/ST-elevation myocardial infarction/non ST-elevation myocardial infarction/ unstable angina, percutaneous coronary intervention without myocardial infarction, and coronary artery bypass graft) and vitals, laboratory tests, and imaging at the time of first CAD event (BMI, systolic blood pressure, diastolic blood pressure, heart rate, chest computed tomography, ejection fraction, global longitudinal strain, atrial size, potassium, aspartate aminotransferase, alanine transaminase, creatinine, glucose, hemoglobin, neutrophil count, lymphocyte count, white blood cell count, C-reactive protein, A1c, total cholesterol, triglycerides, high density lipoprotein, and allostatic load).

Statistical analysis
The data were presented as absolute values and percentages for categorical variables and as median and IQR for continuous variables.Categorical variables were compared using Pearson's x 2 test.Data distribution assumptions for continuous variables were confirmed using histograms and the Kolmogorov-Smirnov test, followed by paired samples t test for normally distributed variables and nonparametric Mann-Whitney U tests for nonnormal distributed variables.To investigate the association between the laterality of BC and CAD, we tested for proportional hazards assumption, then conducted the Cox proportional hazards model with stepwise adjustment and presented the results as hazard ratios (HRs).After presenting the unadjusted model, we adjusted for age and race (model 1).In the subsequent models, we sequentially adjusted for diabetes, hypertension, hypercholesterolemia, BMI, smoking status, and chronic kidney disease (model 2), for CAD (model 3), for cancer stage, type of surgery, radiation dose, hormone therapy, chemotherapy, immunotherapy, and use of HER-2 agents (model 4), and DIBH (model 5 as sensitivity analysis).We additionally conducted a subgroup analysis based on prior CAD versus no prior CAD.A P value of <.05 was considered statistically significant.IBM SPSS and STATA/IC 16.1 (StataCorp) software were used for statistical analysis.

Demographics Meta-analysis
A total of 2301 studies were retrieved from the initial literature search, of which 775 were duplicates and removed.Of the 1526 studies remaining, 42 were included for full-text screening.Of the 42 studies analyzed, 33 were excluded after full-text screening (Fig. 1).A total of 9 studies 6,23-30 were included in the final meta-analysis, involving 118,643 patients (60,947 left-sided and 57,696 right-sided patients) and 6211 CAD events (3347 leftsided events and 2864 right-sided events).Most of the studies analyzed included patients in the age range of 50 to 65 years.[25][26][27][28][29][30] Institutional data set A total of 2692 patients received diagnoses of BC in our institution between January 1, 2010, and January 1, 2022, of whom 1894 patients received EBRT as part of their treatment.Of these, 222 patients with left-sided BC and 245 patients with right-sided BC met the inclusion criteria and were included in the final analysis.The median age at diagnosis was 65 years (IQR, 60-72 years) for patients with left-sided BC and 65 years (IQR, 59-72 years) for patients with right-sided BC.The prevalence of hypertension (92.34% vs 90.20%, P = .415),hypercholesterolemia (59.46% vs 58.61%, P = .852),and diabetes (44.59% vs 40.41%,P = .361)was similar in patients with left-sided versus right-sided BC.There was no significant difference in all-cause mortality (P = .164),or CV mortality (P = .727)based on laterality of BC.The median total radiation dose was 5680 cGy (IQR, 5256-9860 cGy) in patients with left-sided BC and 6040 cGy (IQR, 5256-10,080 cGy) in patients with right-sided BC, with no significant difference in dosage based on laterality of BC (P = .604)(Table 2).The median follow-up time was 2.58 years.

Outcomes Meta-analysis
A pooled random effects model of 9 studies showed that patients with left-sided BC receiving EBRT had a 10% increased risk of CAD when compared with patients with right-sided BC receiving EBRT (RR, 1.10; 95% CI, 1.02-1.18;P = .01)(Fig. 2). 6,23-30A subgroup analysis of 6 studies that included patients who received diagnoses of BC after 1980 did not show a statistically significant difference in CAD based on laterality of BC (RR, 1.07; 95% CI, 0.95-1.20;P = .27)(Fig. 2).Visual inspection of the funnel plot displayed risk for publication bias; hence, a  trim and fill approach was used to adjust for the risk (Fig. E1).The trim and fill random effects model added 2 studies and showed an 11% increased risk of CAD in patients with left-sided BC receiving EBRT (RR, 1.11; 95% CI, 1.04-1.19;P = .002).

Institutional data set
The primary outcome of CAD was noted in 4.95% of patients with left-sided BC and 7.35% of patients with rightsided BC, with no significant difference in incidence based on laterality of BC (P = .284)in totality or based on  zOther is defined as a category comprising patients who in addition to tangential treatment, received radiation to subclavian nodes, posterior axillary boost, or just received partial radiation.
Values are percentages unless noted otherwise.
individual CAD event (Table 2).In an unadjusted model, patients with left-sided BC did not have a significantly higher risk for CAD when compared with patients with right-sided BC (HR, 0.73; 95% CI, 0.34-1.54;P = .402)(Table 3).Similar results were found in subsequent models, including the fully adjusted model (model 4; adjusted hazards ratio, 0.44; 95% CI, 0.06-3.27;P = .420).Among patients with no prior CAD, an unadjusted model showed that patients with left-sided BC did not have a significantly higher risk for CAD when compared with patients with right-sided BC (HR, 0.65; 95% CI, 0.22-1.95;P = .445)(Table 3).Similar results were found in subsequent models.Among patients with prior CAD, an unadjusted model showed that patients with left-sided BC did not have a significantly higher risk for CAD when compared with patients with right-sided BC (HR, 0.99; 95% CI, 0.35-2.78;P = .980).Similar results were found in subsequent models, including when adjusting for DIBH (Table 3, Table E2).

Discussion
This study used contemporary single-institution data along with an updated meta-analysis to determine CAD outcomes in patients who received EBRT for BC based on laterality.Although our meta-analysis demonstrated that patients with left-sided BC were more likely to develop CAD, a more contemporary subgroup analysis of patients diagnosed after 1980 did not show any association between the laterality of BC and CAD outcomes.Our single institutional cohort containing patients diagnosed after 2010 confirmed this finding while also mitigating the limitations of the meta-analysis.We conclude that modern EBRT does not affect CAD outcomes after a BC diagnosis in the short term, even among those with prior CAD.
Our study contributes to the rapidly evolving field of cardio-oncology, which aims to investigate the CV risk associated with cancer therapies and implement treatment strategies to minimize this risk in patients with cancer The findings from this study provide an updated analysis of modern radiation techniques demonstrating no difference in CAD in patients with left-sided versus right-sided BC.[25][26][27][28][29][30] Abbreviations: CAD = coronary artery disease; RR = relative risk.doses of radiation to the heart. 8,36Findings from our institutional cohort reflect these advances, because we found that in the contemporary era, there is no difference in total radiation dose based on the laterality of treatment, which has translated into no difference in risk of CAD based on laterality of EBRT in BC therapy.Over the past decade, there has been increased emphasis on preventative CV care in patients with cancer receiving cardiotoxic therapy.8][39][40] Multidisciplinary cancer care has been established as an essential part of cancer care 41,42 since 1995 42 and has given rise to the rapidly growing field of cardio-oncology. 43,44International guidelines outlining the cardiotoxic effects of cancer therapy [37][38][39][40] as well as the increased number of cancer survivors [37][38][39]45 has led to research outlining the key role of cardio-oncology services 43,[45][46][47] in managing the CV needs of patients currently receiving cancer treatment.By designing our cohort to include patients who received diagnoses of BC after 2010, we aimed to assess whether the increased implementation of preventive care has had a positive effect on CV outcomes.Although the meta-analysis portion of our study and other meta-analyses 48,49 that include patients who received diagnoses of BC in the late 20th century have found an increased CV risk in patients with left-sided BC receiving EBRT, our updated institutional cohort found that in the contemporary era, no such difference in risk occurs.Regardless of the findings of this study, it is evident that real-world patients with BC receiving EBRT have a high burden of CV risk factors and would benefit from cardiooncology screening and management as per guidelines.40,50 This meta-analysis had several limitations. First, te data were based on observational studies rather than randomized control trials.Because the observational data were sourced from country-wide databases, individual patient data were difficult to obtain.Additionally, individual radiation dose information was not available; hence, we could not investigate whether the difference in incidence of CAD events was because of increased radiation dose in left-sided BCs.These limitations are partly offset by the inclusion of the institutional data set.Using this data set allowed us to analyze individual patient information such as demographic information, prior health conditions, cancer information, and radiation information.Additionally, we were able to filter this institutional data set to only include patients diagnosed after 2010 to accurately reflect advances in modern EBRT regimens and implementation of preventative CV care in patients with cancer and analyze its subsequent effect on CAD events.Limitations of the institutional data set include incomplete or unavailable patient information and inconsistent follow-up for some patients.Additionally, our follow-up time was 2.58 years, limiting our ability to draw conclusions about the long-term cardiac effects of radiation.

Conclusion
Our study suggests a historical trend of increased CAD in BC patients receiving left-sided EBRT.However, data from patients diagnosed after 2010 within our institutional cohort did not show a significant difference, emphasizing the potential of modern EBRT regimens, particularly DIBH, to offer a safer alternative.Notably, our findings suggest that the laterality of BC does not significantly affect CAD outcomes in the short term after a BC diagnosis.

Disclosures
Avirup Guha reports a relationship with the American Heart Association that includes: funding grants.Avirup Guha reports a relationship with the Department of Defense that includes: funding grants.Avirup Guha reports a relationship with Pfizer that includes: consulting or advisory.Avirup Guha reports a relationship with Novartis that includes: consulting or advisory.Avirup Guha reports a relationship with Myovant Sciences Inc that includes: consulting or advisory.Avirup Guha reports − leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid − ZERO Prostate Cancer − health equity task force.Susan Dent reports a relationship with AstraZeneca Pharmaceuticals LP that includes: consulting or advisory.Susan Dent reports a relationship with Pfizer that includes: consulting or advisory.Susan Dent reports a relationship with Gilead Sciences Inc that includes: consulting or advisory.Susan Dent reports a relationship with Novartis that includes: consulting or advisory.Ana Barac reports a relationship with CTI BioPharma Corp that includes: board membership.Neal Weintraub reports a relationship with the American Heart Association that includes: travel reimbursement.Rakesh Shiradkar reports a relationship with the Department of Defense that includes: funding grants.Rakesh Shiradkar reports a relationship with Emory University Winship Cancer Institute that includes: funding grants.Rakesh Shiradkar reports a relationship with the National Institutes of Health that includes: funding grants.Anant Madabhushi reports a relationship with Aiforia Inc that includes: consulting fees.Anant Madabhushi reports a relationship with SinbioSys Inc that includes: consulting fees.Anant Madabhushi reports a relationship with Takeda Inc that includes: consulting fees.Anant Madabhushi reports a relationship with Elucid Bioimaging that includes: equity and stock ownership.Anant Madabhushi reports a relationship with Inspirata Inc that includes: equity and stock ownership.Anant Madabhushi reports a relationship with Picture Health that includes: board membership and equity and stock ownership.The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figure 1
Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram of the meta-analysis of the risk of coronary artery disease events in breast cancer patients receiving left-sided external beam radiation therapy versus right-sided external beam radiation therapy.

Abbreviations:
Abbreviations: BMI = body mass index; CABG = coronary artery bypass graft; CAD events = coronary artery disease events; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; CVA = cerebrovascular accident; DIBH = deep inspiration breath hold; MI = myocardial infarction; NSTEMI = non−ST-elevation myocardial infarction; PAD = peripheral artery disease; PCI = percutaneous coronary intervention; STEMI = STelevation myocardial infarction; TIA = transient ischemic attack.*Signifies a statistically significant p value (p < 0.05).yA 2-sided Fisher exact test was used to obtain this P value because the x 2 assumption was violated because of fewer than 5 expected counts in >1 cell.zOther is defined as a category comprising patients who in addition to tangential treatment, received radiation to subclavian nodes, posterior axillary boost, or just received partial radiation.Values are percentages unless noted otherwise.

Table 1
Baseline characteristics of the studies included in the meta-analysis

Table 2
Baseline characteristics and CAD events from our institutional cohort

Table 3
Cox proportional hazards model for the outcome of CAD in the entire cohort, those with no prior CAD and those with prior CAD HR (95% CI, P value)